Administration of ethyl 3-[(2--1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate

ABSTRACT

The invention relates to a new administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Ser. No. 60/421,896, filed onOct. 29, 2002 and U.S. Provisional Application Ser. No. 60/409,762,filed on Sep. 11, 2002 is hereby claimed, and said applications areherein incorporated by reference.

FIELD OF INVENTION

The invention relates to administration forms for oral applications ofprodrugs and in particular prodrugs of the active substance ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionateand the pharmacologically acceptable salts thereof.

BACKGROUND OF THE INVENTION

The invention relates to an administration form for the oral applicationof the active substance ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionateand the pharmacologically acceptable salts thereof. This activesubstance having the chemical formula

is already known from WO 98/37075, which discloses compounds with athrombin-inhibiting effect and the effect of prolonging the thrombintime, under the name1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazole-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amides. The compound offormula I is a double prodrug of the compound

i.e. the compound of formula I is only converted into the activecompound, namely the compound of formula II, after entering the body.The main indication for the compound of chemical formula I is thepost-operative prevention of deep-vein thrombosis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic structure of the pharmaceutical composition.

FIG. 2 shows the bioavailability of BIBR 1048.

DESCRIPTION OF THE INVENTION

The aim of the invention is to provide an improved formulation for oraluse of the compound of formula I (which is also referred to hereinafteras the “active substance”).

Surprisingly it has now been found that the use of pharmaceuticallyacceptable organic acids with a water solubility of >1 g/250 ml at 20°C., preferably >1 g/160 ml at 25° C., in solid oral preparations leadsto a significantly improved formulation of ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionateas well as the pharmaceutically acceptable salts thereof.

Pharmaceutically suitable acids for the purposes of this invention arefor example tartaric acid, fumaric acid, succinic acid, citric acid,malic acid, glutamic acid and aspartic acid including the hydrates andacid salts thereof. Particularly suitable for the purposes of thisinvention are tartaric acid, fumaric acid, succinic acid and citricacid.

A preferred embodiment of the invention is a multiparticulatepreparation in which the individual particles are constructed as in FIG.1.

FIG. 1 shows the diagrammatic structure of the pharmaceuticalcomposition by means of a section through a pellet suitable for thepreparation of the pharmaceutical composition according to theinvention. The roughly bead-shaped/spherical core region of this pelletcontains/consists of the pharmaceutically acceptable organic acid. Thenfollows a layer, the so-called insulating layer, which separates theacid core from the layer containing the active substance. The insulatinglayer is in turn surrounded by the equally spherically shaped layer ofactive substance which may in turn be enclosed in a coating whichincreases the abrasion resistance and shelf life of the pellets.

One advantage of the formulation thus constructed is the spatialseparation of the organic acid and active substance by the insulatinglayer. A further advantage of the construction of the pellets asdescribed above is the fact that the organic acid does not go intosolution until after the preparation has been taken and then produces anacid microclimate in which the active substance can dissolve.

The core material used is a pharmaceutically acceptable organic acidwith a water solubility of >1 g/250 ml at 20° C., such as e.g. tartaricacid, fumaric acid, succinic acid, citric acid, malic acid, glutamicacid and aspartic acid including the hydrates and acid salts thereof, towhich a small amount of 1 to 10% by weight, preferably 3 to 6% by weightof a suitable binder is optionally added. The use of a binder may benecessary, for example, if the starting acids are produced by a panbuild-up process. If the method used is extrusion or spheronisation,other technological adjuvants such as microcrystalline cellulose will beneeded instead of binders. It is also possible to use pure (100%) acidas the starting material if it can be obtained in a sufficiently narrowrange of particle sizes. The pharmaceutically acceptable organic acidsused are preferably tartaric acid, fumaric acid, succinic acid or citricacid; tartaric acid is particularly preferred. As binder, it is possibleto use gum arabic or a partially or totally synthetic polymer selectedfrom among the hydroxypropylcelluloses, hydroxypropylmethylcelluloses,methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses,polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinylacetate, or combinations of these polymers; gum arabic is preferred. Thespherical core material preferably has an average diameter of 0.4-1.5mm. The content of the pharmaceutically acceptable organic acid isusually between 30 and 100% in the core material, corresponding to anamount of between 20 and 90%, preferably between 20 and 80% in thefinished pellet (i.e. in the pharmaceutical composition).

To increase the durability of the finished product it is advantageous tocoat the core material before the application of the active substancewith an insulating layer based on a water-soluble, pharmaceuticallyacceptable polymer. Examples of such water-soluble polymers include forexample gum arabic or a partially or totally synthetic polymer selectedfrom among the hydroxypropylcelluloses, hydroxypropylmethylcelluloses,methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses,polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinylacetate, or combinations of these polymers. Gum arabic or ahydroxypropylmethylcellulose is preferably used. If desired, the coatingwith the water-soluble, pharmaceutically acceptable polymer may becarried out with the addition of suitable plasticisers, separatingagents and pigments, such as for example triethylcitrate,tributylcitrate, triacetin, polyethyleneglycols (plasticisers), talc,silicic acid (separating agents), titanium dioxide or iron oxidepigments (pigments).

The active substance layer contains the active substance ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate(BIBR 1048) or one of the pharmaceutically acceptable salts thereof aswell as binders and optionally separating agents. A preferred salt ofthe active substance is the mesylate (methanesulphonate) of the compoundof formula I. Suitable binders include for examplehydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone,copolymers of N-vinylpyrrolidone and vinyl acetate or combinations ofthese polymers. Preferably, hydroxypropylcellulose or copolymers ofN-vinylpyrrolidone and vinyl acetate are used. The addition ofseparating agents such as e.g. talc or silicic acid serves to preventthe particles from aggregating during the process. The active substancecontent is 5 to 60%, preferably 10 to 50% of the pharmaceuticalcomposition.

The optional outermost layer, which serves to reduce any increasedabrasion during packing into capsules and/or to increase the shelf life,consists of pharmaceutically conventional film-forming agents,plasticisers and optionally pigments. Suitable film-forming agentsinclude for example hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, polymers and copolymersof acrylic and methacrylic acid and the esters thereof, or combinationsof these polymers. Suitable plasticisers include inter aliatriethylcitrate, tributylcitrate, triacetin or polyethyleneglycols. Thepigments used may be e.g. titanium dioxide or iron oxide pigments.Preferably, the outer coating consists of hydroxypropylmethylcelluloseand/or methylcellulose, optionally with the addition ofpolyethyleneglycols as plasticisers.

The pellets may be prepared by the method described hereinafter:

The acid-containing core material consists either of crystals of theparticular organic acid used or, more advantageously, of roughlyspherical particles of the desired size containing a large amount oforganic acid, which can be produced by methods known and established inpharmaceutical technology. The core material may be produced, inparticular, by pan methods, on pelleting plates or byextrusion/spheronisation. Then the core material thus obtained may bedivided into fractions of the desired diameter by screening. Suitablecore material has an average diameter of 0.4 to 1.5 mm, preferably 0.6to 0.8 mm.

First, the insulating layer is applied to this acid-containing corematerial. This can be done by conventional methods, e.g. by applying anaqueous dispersion of the water-soluble, pharmaceutically acceptablepolymer, optionally with the addition of plasticisers, separating agentsand/or pigments, in a fluidised bed, in coating pans or in conventionalfilm coating apparatus. If necessary the product can then be screenedagain.

Then the active substance is applied from a dispersion containing binderand optionally separating agent. The volatile dispersant is removedduring or after the process by drying. Suitable binders in thedispersion may be for example hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, copolymers ofN-vinylpyrrolidone and vinyl acetate or combinations of these polymers.Preferably, hydroxypropylcellulose or copolymers of N-vinylpyrrolidoneand vinyl acetate are used. Suitable separating agents include e.g. talcor silicic acid; preferably, talc is used. The dispersants may be forexample ethanol, 2-propanol, acetone or mixtures of these solvents withone another or with water, preferably 2-propanol. The application ofactive substance to the core material may be carried out by establishedmethods known in pharmaceutical technology, e.g. in coating pans,conventional film coating apparatus or by the fluidised bed method. Thena further screening process may be carried out.

To reduce any increased abrasion during transfer into capsules or toincrease the shelf life the system may finally be coated with a coatingof a pharmaceutically conventional film forming agent, plasticiser andoptionally pigment. This may be done by conventional methods asmentioned earlier in the description of the application of theinsulating layer.

When core material with an average diameter of 0.4-1.5 mm is used, theprocess described above produces pellets containing active substance,which can then be packed into hard capsules, for example. To do this, anumber of these units corresponding to the required dosage are packedinto hard capsules in a standard capsule filling machine. Suitable hardcapsules include, for example, hard gelatine capsules or hard capsulesof hydroxypropylmethylcellulose (HPMC); HPMC capsules are preferred. Theactive substance content of the pharmaceutical composition is 5 to 60%,preferably 10 to 50%; the content of the pharmaceutically acceptableorganic acid is usually between 20 and 90%, preferably between 20 and80%.

Unless otherwise stated, percentages specified are always percent byweight. All the data on the active substance content relate to theactive substance base of formula I (not to a specific salt) unlessotherwise stated.

Clinical Trials

In preliminary tests on test subjects with conventional tabletscontaining the compound of formula I it had been established that highlyvariable plasma levels occurred, with individual cases of malabsorption.The variability of the plasma level patterns is significantly lowerafter the administration of the compound of formula I as an orallyadministered solution; there were no cases of malabsorption under thesecircumstances.

Tests have shown that the compound of formula I dissolves relativelywell in water at low pH levels, whereas at pH levels above 5 inaccordance with the definition of the European Pharmacopoeia it isvirtually insoluble. Therefore the volunteers in one branch of theclinical trials were given pantoprazole, which serves to produce anelevated gastric pH.

For example, the pharmaceutical compositions according to Examples 1 and2 were tested for their bioavailability by comparison with aconventional tablet. To do this, the formulation prepared according toExample 1 containing 50 mg of active substance base per capsule wasclinically tested for its bioavailability on a total of 15 volunteers.In one branch of the treatment, the volunteers were given thecomposition by mouth (=orally) on an empty stomach without anypre-treatment. In another branch of the treatment the same volunteerswere pre-treated, prior to the oral administration of the composition,with 40 mg of pantoprazole b.i.d. (=twice a day) for three days by mouthto increase the gastric pH; the treatment with pantoprazole wascontinued during the administration of the formulation according to theinvention.

The degree of absorption was determined by measuring the quantity ofactive metabolite of formula II excreted in the urine.

The relative bioavailability after pre-treatment with pantoprazole was94% on average compared with administration without any pre-treatment.

Under comparable conditions of administration, the relativebioavailability (based on the area under the plasma concentration/timecurve) of a tablet containing 50 mg of active substance, developed andproduced according to the prior art and containing no water-solubleorganic acid, after corresponding pre-treatment with pantoprazole, is18%. Table I shows the precise composition of the tablet used:

TABLE I Ingredient mg/tablet Core mesylate of the compound of form. I57.7 lactose monohydrate 58.0 microcrystalline cellulose 48.3crospovidone 3.4 magnesium stearate 2.6 Film coating polyethyleneglycol6000 0.56 titanium dioxide 0.80 talc 0.64 hydroxypropylmethylcellulose1.92 iron oxide yellow 0.08 Total 174.0

The relative bioavailability was thus improved by about a factor of 5 byusing the formulation according to the invention.

The formulation prepared according to Example 2 containing 50 mg ofactive substance base per capsule was also clinically tested for itsbioavailability on a total of 15 volunteers. In one branch of thetreatment, the volunteers were given the composition by mouth on anempty stomach without any pre-treatment. In another branch of thetreatment the same volunteers were pre-treated, prior to the oraladministration of the composition, with 40 mg of pantoprazole b.i.d. forthree days by mouth to increase the gastric pH; the treatment withpantoprazole was continued during the administration of the formulationaccording to the invention.

The degree of absorption was determined by measuring the quantity of theactive metabolite of formula II excreted in the urine.

The relative bioavailability after pre-treatment with pantoprazole was76% on average compared with administration without any pre-treatment.

Under comparable conditions of administration, the relativebioavailability (based on the area under the plasma concentration/timecurve) of a tablet containing 50 mg of active substance, developed andproduced according to the prior art and containing no water-solubleorganic acid, after corresponding pre-treatment with pantoprazole, is18%. Table II shows the precise composition of the tablet used:

TABLE II Ingredient mg/tablet Core mesylate of the compound of form. I57.7 lactose monohydrate 58.0 microcrystalline cellulose 48.3crospovidone 3.4 magnesium stearate 2.6 Film coating polyethyleneglycol6000 0.56 titanium dioxide 0.80 talc 0.64 hydroxypropylmethylcellulose1.92 iron oxide yellow 0.08 Total 174.0

The relative bioavailability of the active substance compared withconventional formulations was thus improved by about a factor of 4 byusing the formulation according to the invention. The bioavailability ofthe two formulations according to the invention compared with the tabletdescribed above with and without the simultaneous administration ofpantoprazole is graphically illustrated in FIG. 2.

The clinical trials show another advantage of the preparation accordingto the invention containing the compound of formula I, which is that itensures adequate bioavailability of the active substance, better thanthat of a conventional pharmaceutical preparation and largelyindependent of the gastric pH, it reduces fluctuations in thebioavailability of the active substance and it prevents malabsorption.Another advantageous property of the pharmaceutical compositionaccording to the invention is the fact that it is suitable for allpatients, i.e. including those in whom the gastric pH is increased bynormal physiological variability, by disease or by co-medication withdrugs which raise the gastric pH.

The dosage for oral use is expediently 25 to 300 mg of the activesubstance base (per capsule), preferably 50 to 200 mg, most preferably75 to 150 mg of the active substance base, in each case once or twice aday.

The preferred ratio of acid to active substance is about 0.9:1 to about4:1, most preferably between about 1:1 and 3:1. Preferably, at least oneequivalent of acid is used per mol of the compound of formula I. Theupper limit of about 4:1 (acid to active substance) is generallydetermined by the maximum acceptable size of the preparation in thedesired dosages (number of pellets per capsule).

The Examples that follow are intended to illustrate the invention:

EXAMPLE 1

percentage composition insulat- active per per core ing substancecapsule capsule material layer layer total [mg] [mg] tartaric acid 61.3— — 61.3 176.7 353.4 gum arabic 3.1 2.8 5.9 17.0 34.0 talc — 5.6 3.2 8.825.4 50.7 hydroxy- — — 4.0 4.0 11.5 23.1 propylcellulose activesubstance — — 20.0 20.0 57.7* 115.3** (mesylate of the compound offormula I) total 100.0 288.3 576.5 *) corresponds to 50 mg of thecompound of formula 1 (active substance base) **) corresponds to 100 mgof the compound of formula 1 (active substance base)

a) Production of core material containing tartaric acid

Composition:

gum arabic  1 part by weight tartaric acid 20 parts by weight

1 part by weight of gum arabic is dissolved In 4 parts by weight ofpurified water at 50° C. with stirring. Then 5 parts by weight oftartaric acid are dissolved in this solution with stirring.

8.3 parts by weight of tartaric acid crystals with an average particlesize of 0.4 to 0.6 mm are placed in a suitable coating apparatus fittedwith an air inlet and exhaust, and the pan is set in rotation. At an airinlet temperature of 60°-80° C. the tartaric acid crystals are sprayedat intervals with the solution of tartaric acid and gum arabic andsprinkled with a total of 6.7 parts by weight of powdered tartaric acid,so that roughly spherical particles are formed.

The spherical tartaric acid core material is then dried in the rotatingpan at an air inlet temperature of 60°-80° C.

The core material is fractionated using a tumbler screening machine withperforated plates with a nominal mesh size of 0.6 and 0.8 mm. Theproduct fraction between 0.6 and 0.8 mm is used in the rest of theprocess.

b) Insulation of the core material containing tartaric acid

Composition:

core material containing tartaric acid 23 parts by weight gum arabic  1part by weight talc  2 parts by weight

1 part by weight of gum arabic is dissolved in a mixture of 6.7 parts byweight of 96% ethanol and 13.5 parts by weight of purified water withstirring. Then 2 parts by weight of talc are dispersed in the solutionwith stirring.

In a fluidised bed processing apparatus, 23 parts by weight of corematerial containing tartaric acid are sprayed at an air inlettemperature of 35°-40° C. with the dispersion of gum arabic and talc bythe under-bed spraying process.

The insulated core material containing tartaric acid is then dried inthe circulating air drier at 40° C. for 8 hours.

To remove any lumps the dried insulated core material containingtartaric acid is screened through a screen with a nominal mesh size of1.0 mm. The fraction of material with a particle size of <1 mm isfurther processed.

c) Production of the active substance layer

Composition:

insulated core material containing tartaric acid 91 parts by weighthydroxypropylcellulose  5 parts by weight talc  4 parts by weight activesubstance (mesylate of BIBR 1048) 25 parts by weight

Hydroxypropylcellulose is dissolved in 168 parts by weight of 2-propanolwith stirring and then the active substance and talc are dispersed inthis solution with stirring.

In a fluidised bed processing apparatus, 91 parts by weight of insulatedcore material containing tartaric acid are sprayed at an air inlettemperature of 20°-30° C. with the dispersion containing the activesubstance by the under-bed spraying process.

The pellets containing the active substance are then dried in thecirculating air drier at 35° C. for 8 hours.

To remove any lumps the pellets containing the active substance arescreened through a screen with a nominal mesh size of 1.25 mm. Thefraction of material with a particle size of <1.25 mm is furtherprocessed.

d) Packing into capsules

A quantity of active substance pellets containing in each case 50 or 100mg of active substance base is packed into size 1 or size 0 elongatedhard gelatine capsules or HPMC capsules by means of a capsule fillingmachine.

EXAMPLE 2

percentage composition insulat- active per per core ing substancecapsule capsule material layer layer total [mg] [mg] tartaric acid 38.5— — 38.5 55.5 166.5 gum arabic 1.9 1.7 3.6 5.2 15.6 talc — 3.5 6.4 9.914.3 42.8 hydroxy- — — 8.0 8.0 11.5 34.6 propylcellulose activesubstance — — 40.0 40.0 57.7* 173.0** (mesylate of the compound offormula I) total 100.0 144.2 432.5 *) corresponds to 50 mg of thecompound of formula 1 (active substance base) **) corresponds to 150 mgof the compound of formula 1 (active substance base)

a) Production of core material containing tartaric acid

Composition:

gum arabic  1 part by weight tartaric acid 20 parts by weight

1 part by weight of gum arabic is dissolved in 4 parts by weight ofpurified water at 50° C. with stirring. Then 5 parts by weight oftartaric acid are dissolved in this solution with stirring.

8.3 parts by weight of tartaric acid crystals with an average particlesize of 0.4 to 0.6 mm are placed in a suitable coating apparatus fittedwith an air inlet and exhaust, and the pan is set in rotation. At an airinlet temperature of 60°-80° C. the tartaric acid crystals are sprayedat intervals with the solution of tartaric acid and gum arabic andsprinkled with a total of 6.7 parts by weight of powdered tartaric acid,so that roughly spherical particles are formed.

The spherical tartaric acid core material is then dried in the rotatingpan at an air inlet temperature of 60°-80° C.

The core material is fractionated using a tumbler screening machine withperforated plates with a nominal mesh size of 0.6 and 0.8 mm. Theproduct fraction between 0.6 and 0.8 mm is used in the rest of theprocess.

b) Insulation of the core material containing tartaric acid

Composition:

core material containing tartaric acid 23 parts by weight gum arabic  1part by weight talc  2 parts by weight

1 part by weight of gum arabic is dissolved in a mixture of 6.7 parts byweight of 96% ethanol and 13.5 parts by weight of purified water withstirring. Then 2 parts by weight of talc are dispersed in the solutionwith stirring.

In a fluidised bed processing apparatus, 23 parts by weight of corematerial containing tartaric acid are sprayed at an air inlettemperature of 35°-40° C. with the dispersion of gum arabic and talc bythe under-bed spraying process.

The insulated core material containing tartaric acid is then dried inthe circulating air drier at 40° C. for 8 hours.

To remove any lumps the dried insulated core material containingtartaric acid is screened through a screen with a nominal mesh size of1.0 mm. The fraction of material with a particle size of <1 mm isfurther processed.

c) Production of the active substance layer

Composition:

insulated core material containing tartaric acid 57 parts by weighthydroxypropylcellulose 10 parts by weight talc  8 parts by weight activesubstance (mesylate of BIBR 1048) 50 parts by weight

Hydroxypropylcellulose is dissolved in 335 parts by weight of 2-propanolwith stirring and then the active substance and talc are dispersed inthis solution with stirring.

In a fluidised bed processing apparatus, 91 parts by weight of insulatedcore material containing tartaric acid are sprayed at an air inlettemperature of 20°-30° C. with the dispersion containing the activesubstance by the under-bed spraying process.

The pellets containing the active substance are then dried in thecirculating air drier at 35° C. for 8 hours.

To remove any lumps the pellets containing the active substance arescreened through a screen with a nominal mesh size of 1.25 mm. Thefraction of material with a particle size of <1.25 mm is furtherprocessed.

d) Packing into capsules

A quantity of active substance pellets containing in each case 50 or 150mg of active substance base is packed into size 2 or size 0 hardgelatine capsules or HPMC capsules by means of a capsule fillingmachine.

EXAMPLE 3

Preparation of ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionatemethanesulphonate

A solution of 5.0 mmol of methanesulphonic acid in 25 ml ethyl acetatewas added dropwise, with stirring, to a solution of 3139 mg (5.0 mmol)of ethyl3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionatebase (prepared as described in WO 98/37075) in 250 ml ethyl acetate, atambient temperature. After a few minutes the product began tocrystallise out. It was stirred for another hour at ambient temperatureand then for one more hour while cooling with ice, the precipitate wassuction filtered, washed with about 50 ml of ethyl acetate and 50 ml ofdiethyl ether and dried at 50° C. in a circulating air drier.

Yield: 94% of theory melting point: 178-179° C. C₃₄H₄₁N₇O₅×CH₄SO₃(723.86)

Elemental analysis: C H N S calc.: 58.07% 6.27% 13.55% 4.43% found:58.11% 6.30% 13.50% 4.48%

1-16. (canceled)
 17. A method to inhibit thrombin in a patient in needthereof comprising administering a methanesulphonate salt of ethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateto the patient such that the patient receives an oral dose from 50 mg to200 mg of ethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateonce or twice a day.
 18. A method to inhibit thrombin in a patient inneed thereof comprising administering a methanesulphonate salt of ethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateto the patient such that the patient receives an oral dose from 75 mg to150 mg of ethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateonce or twice a day.
 19. A method to inhibit thrombin in a patient inneed thereof comprising administering a methanesulphonate salt of ethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateto the patient such that the patient receives an oral dose of 150 mg ofethyl3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionateonce or twice a day.